Management of severe refractory atopic dermatitis (eczema)
- Jonathan M Spergel, MD, PhD, FAAAAI
Jonathan M Spergel, MD, PhD, FAAAAI
- Professor of Pediatrics
- University of Pennsylvania School of Medicine
- Section Editors
- Robert P Dellavalle, MD, PhD, MSPH
Robert P Dellavalle, MD, PhD, MSPH
- Section Editor — General Dermatology
- Professor of Dermatology and Public Health
- University of Colorado School of Medicine
- Colorado School of Public Health
- Chief, Dermatology Service
- US Department of Veterans Affairs
- Eastern Colorado Health Care System
- Moise L Levy, MD
Moise L Levy, MD
- Section Editor — Pediatric Dermatology
- Professor of Pediatrics and Medicine (Dermatology)
- Dell Medical School, University of Texas, Austin
- Clinical Professor of Dermatology and Pediatrics
- Baylor College of Medicine
- Joseph Fowler, MD
Joseph Fowler, MD
- Section Editor — Dermatitis
- Clinical Professor of Dermatology
- University of Louisville School of Medicine
Atopic dermatitis is a common, chronic, inflammatory skin disorder characterized by the presence of pruritic eczematous dermatitis. In most patients, the disorder is managed with careful skin care practices, topical therapies for inflammation, and the elimination of exacerbating factors. Patients with severe disease that fails to improve with conventional therapy may benefit from phototherapy or systemic medications.
This topic reviews the causes and treatment of severe, refractory atopic dermatitis. The clinical manifestations, diagnosis, and conventional management of the disease and the role of allergy in atopic dermatitis are discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema)" and "Treatment of atopic dermatitis (eczema)" and "Role of allergy in atopic dermatitis (eczema)".)
SEVERE ATOPIC DERMATITIS
Most patients with atopic dermatitis have mild to moderate disease. However, a subpopulation of patients develops severe symptoms. Severe atopic dermatitis may be loosely described as the presence of widespread skin lesions or physically or emotionally disabling disease that significantly compromises a patient's quality of life (picture 1).
Clinical studies have utilized scales for defining the severity of atopic dermatitis, such as the Severity Scoring of Atopic Dermatitis (SCORAD) index and the Eczema Area and Severity Index (EASI) . Although such scales are useful for standardizing the results of research studies, they are not routinely used in clinical practice. Patients with severe atopic dermatitis who do not respond to conventional therapy may be classified as having severe, refractory disease.
Prior to initiating second-line treatments for atopic dermatitis, clinicians must ensure that severe, refractory disease is not a result of the presence of an avoidable or treatable exacerbating factor. Circumstances that may contribute to severe or refractory atopic dermatitis include non-compliance with conventional therapy, secondary infection, hypersensitivity reactions to topical treatments, and exposure to triggers of disease flares.
- Schmitt J, Langan S, Deckert S, et al. Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin Immunol 2013; 132:1337.
- Beattie PE, Lewis-Jones MS. Parental knowledge of topical therapies in the treatment of childhood atopic dermatitis. Clin Exp Dermatol 2003; 28:549.
- Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol 2006; 118:226.
- Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to topical medication: adherence is very poor in children with atopic dermatitis. J Am Acad Dermatol 2007; 56:211.
- Ohya Y, Williams H, Steptoe A, et al. Psychosocial factors and adherence to treatment advice in childhood atopic dermatitis. J Invest Dermatol 2001; 117:852.
- Karlberg AT, Bergström MA, Börje A, et al. Allergic contact dermatitis--formation, structural requirements, and reactivity of skin sensitizers. Chem Res Toxicol 2008; 21:53.
- Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis 2008; 19:38.
- Iliev D, Wüthrich B. Occupational protein contact dermatitis with type I allergy to different kinds of meat and vegetables. Int Arch Occup Environ Health 1998; 71:289.
- Lodén M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol 2003; 4:771.
- Pirker C, Möslinger T, Wantke F, et al. Ethylmercuric chloride: the responsible agent in thimerosal hypersensitivity. Contact Dermatitis 1993; 29:152.
- VanArsdel PP Jr, Larson EB. Diagnostic tests for patients with suspected allergic disease. Utility and limitations. Ann Intern Med 1989; 110:304.
- Corazza M, Mantovani L, Maranini C, et al. Contact sensitization to corticosteroids: increased risk in long term dermatoses. Eur J Dermatol 2000; 10:533.
- Mailhol C, Lauwers-Cances V, Rancé F, et al. Prevalence and risk factors for allergic contact dermatitis to topical treatment in atopic dermatitis: a study in 641 children. Allergy 2009; 64:801.
- Gambichler T. Management of atopic dermatitis using photo(chemo)therapy. Arch Dermatol Res 2009; 301:197.
- BuBmann C, Bieber T, Novak N. Systemic therapeutic options for severe atopic dermatitis. J Dtsch Dermatol Ges 2009; 7:205.
- Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 2006; 61:969.
- Schmitt J, Schäkel K, Schmitt N, Meurer M. Systemic treatment of severe atopic eczema: a systematic review. Acta Derm Venereol 2007; 87:100.
- Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 2007; 56:e55.
- Jung T, Stingl G. Atopic dermatitis: therapeutic concepts evolving from new pathophysiologic insights. J Allergy Clin Immunol 2008; 122:1074.
- Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric population. Pediatrics 2008; 122:812.
- Meduri NB, Vandergriff T, Rasmussen H, Jacobe H. Phototherapy in the management of atopic dermatitis: a systematic review. Photodermatol Photoimmunol Photomed 2007; 23:106.
- Garritsen FM, Brouwer MW, Limpens J, Spuls PI. Photo(chemo)therapy in the management of atopic dermatitis: an updated systematic review with implications for practice and research. Br J Dermatol 2014; 170:501.
- Reynolds NJ, Franklin V, Gray JC, et al. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 2001; 357:2012.
- Hjerppe M, Hasan T, Saksala I, Reunala T. Narrow-band UVB treatment in atopic dermatitis. Acta Derm Venereol 2001; 81:439.
- von Kobyletzki G, Pieck C, Hoffmann K, et al. Medium-dose UVA1 cold-light phototherapy in the treatment of severe atopic dermatitis. J Am Acad Dermatol 1999; 41:931.
- Tzaneva S, Kittler H, Holzer G, et al. 5-Methoxypsoralen plus ultraviolet (UV) A is superior to medium-dose UVA1 in the treatment of severe atopic dermatitis: a randomized crossover trial. Br J Dermatol 2010; 162:655.
- Stern RS, PUVA Follow up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44:755.
- Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: a cohort study. J Invest Dermatol 2003; 121:252.
- Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of malignancy. J Am Acad Dermatol 2009; 60:1001.
- Tay YK, Morelli JG, Weston WL. Experience with UVB phototherapy in children. Pediatr Dermatol 1996; 13:406.
- Jury CS, McHenry P, Burden AD, et al. Narrowband ultraviolet B (UVB) phototherapy in children. Clin Exp Dermatol 2006; 31:196.
- Clayton TH, Clark SM, Turner D, Goulden V. The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy. Clin Exp Dermatol 2007; 32:28.
- Shaw MG, Burkhart CN, Morrell DS. Systemic therapies for pediatric atopic dermatitis: a review for the primary care physician. Pediatr Ann 2009; 38:380.
- Akhavan A, Rudikoff D. Atopic dermatitis: systemic immunosuppressive therapy. Semin Cutan Med Surg 2008; 27:151.
- Sowden JM, Berth-Jones J, Ross JS, et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991; 338:137.
- Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema - a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007; 21:606.
- Brazzelli V, Prestinari F, Chiesa MG, et al. Sequential treatment of severe atopic dermatitis with cyclosporin A and low-dose narrow-band UVB phototherapy. Dermatology 2002; 204:252.
- Mrowietz U. Macrolide immunosuppressants. Eur J Dermatol 1999; 9:346.
- Zonneveld IM, De Rie MA, Beljaards RC, et al. The long-term safety and efficacy of cyclosporin in severe refractory atopic dermatitis: a comparison of two dosage regimens. Br J Dermatol 1996; 135 Suppl 48:15.
- Haeck IM, Knol MJ, Ten Berge O, et al. Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol 2011; 64:1074.
- Grundmann-Kollmann M, Podda M, Ochsendorf F, et al. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001; 137:870.
- Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol 2001; 144:638.
- Hansen ER, Buus S, Deleuran M, Andersen KE. Treatment of atopic dermatitis with mycophenolate mofetil. Br J Dermatol 2000; 143:1324.
- Grundmann-Kollmann M, Korting HC, Behrens S, et al. Successful treatment of severe refractory atopic dermatitis with mycophenolate mofetil. Br J Dermatol 1999; 141:175.
- Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 2007; 32:23.
- Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol 2000; 143:385.
- Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007; 157:127.
- Berth-Jones J, Takwale A, Tan E, et al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol 2002; 147:324.
- Hon KL, Ching GK, Leung TF, et al. Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults. J Dermatolog Treat 2009; 20:141.
- Hughes R, Collins P, Rogers S. Further experience of using azathioprine in the treatment of severe atopic dermatitis. Clin Exp Dermatol 2008; 33:710.
- Schram ME, Roekevisch E, Leeflang MM, et al. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol 2011; 128:353.
- Flohr C, Irvine AD. Systemic therapies for severe atopic dermatitis in children and adults. J Allergy Clin Immunol 2013; 132:774.
- Fuggle NR, Bragoli W, Mahto A, et al. The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. J Am Acad Dermatol 2015; 72:108.
- Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 2007; 156:346.
- Borchard KL, Orchard D. Systemic therapy of paediatric atopic dermatitis: an update. Australas J Dermatol 2008; 49:123.
- Wozel G, Vitéz L, Pfeiffer C. Severe atopic dermatitis and leflunomide: first clinical experience and highlights of pertinent experimental data. Dermatol Online J 2006; 12:6.
- Schmitt J, Wozel G, Pfeiffer C. Leflunomide as a novel treatment option in severe atopic dermatitis. Br J Dermatol 2004; 150:1182.
- Belloni B, Andres C, Ollert M, et al. Novel immunological approaches in the treatment of atopic eczema. Curr Opin Allergy Clin Immunol 2008; 8:423.
- Sanchez J, Ramirez R, Diez S, et al. Omalizumab beyond asthma. Allergol Immunopathol (Madr) 2012; 40:306.
- Sheinkopf LE, Rafi AW, Do LT, et al. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study. Allergy Asthma Proc 2008; 29:530.
- Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007; 120:1223.
- Simon D, Hösli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 2008; 121:122.
- Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2005; 52:522.
- Simon D, Wittwer J, Kostylina G, et al. Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema. J Allergy Clin Immunol 2008; 122:423.
- Moul DK, Routhouska SB, Robinson MR, Korman NJ. Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 2008; 58:984.
- Buka RL, Resh B, Roberts B, et al. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol 2005; 53:358.
- Rullan P, Murase J. Two cases of chronic atopic dermatitis treated with soluble tumor necrosis factor receptor therapy. J Drugs Dermatol 2009; 8:873.
- Hanifin JM, Schneider LC, Leung DY, et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993; 28:189.
- Schneider LC, Baz Z, Zarcone C, Zurakowski D. Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis. Ann Allergy Asthma Immunol 1998; 80:263.
- Reinhold U, Kukel S, Brzoska J, Kreysel HW. Systemic interferon gamma treatment in severe atopic dermatitis. J Am Acad Dermatol 1993; 29:58.
- Jang IG, Yang JK, Lee HJ, et al. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol 2000; 42:1033.
- Noh GW, Lee KY. Blood eosinophils and serum IgE as predictors for prognosis of interferon-gamma therapy in atopic dermatitis. Allergy 1998; 53:1202.
- Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 2005; 60:693.
- Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 2014; 371:130.
- Prinz B, Nachbar F, Plewig G. Treatment of severe atopic dermatitis with extracorporeal photopheresis. Arch Dermatol Res 1994; 287:48.
- Richter HI, Billmann-Eberwein C, Grewe M, et al. Successful monotherapy of severe and intractable atopic dermatitis by photopheresis. J Am Acad Dermatol 1998; 38:585.
- Prinz B, Michelsen S, Pfeiffer C, Plewig G. Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis. J Am Acad Dermatol 1999; 40:577.
- Radenhausen M, Michelsen S, Plewig G, et al. Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal photochemotherapy. J Dermatol 2004; 31:961.
- Sand M, Bechara FG, Sand D, et al. Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis. Dermatology 2007; 215:134.
- Wolf P, Georgas D, Tomi NS, et al. Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from a prospective trial. Photochem Photobiol Sci 2013; 12:174.
- Rubegni P, Poggiali S, Cevenini G, et al. Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal photochemotherapy. J Eur Acad Dermatol Venereol 2013; 27:523.
- Jolles S. A review of high-dose intravenous immunoglobulin treatment for atopic dermatitis. Clin Exp Dermatol 2002; 27:3.
- SEVERE ATOPIC DERMATITIS
- EXACERBATING FACTORS
- Poor compliance
- Environmental triggers
- Hypersensitivity reactions to treatment
- Food and environmental allergies
- DIFFERENTIAL DIAGNOSIS
- GENERAL APPROACH TO TREATMENT
- Narrowband UVB
- Ultraviolet A1
- Psoralen plus UVA
- Broadband UVA and UVB
- In children
- SYSTEMIC IMMUNOSUPPRESSANTS
- Mycophenolate mofetil
- Systemic corticosteroids
- OTHER THERAPIES
- Extracorporeal photopheresis
- Intravenous immune globulin
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS